FR2609394A1 - AQUEOUS SOLUTION CONTAINING QUINOLONE CARBOXYLIC ACID - Google Patents

Abstract

A STABLE ISOTONIC AQUEOUS SOLUTION IS DESCRIBED WHICH ESSENTIALLY INCLUDES: - AN EFFECTIVE MICROBICIDE QUANTITY OF THE COMPOUND WHICH IS THE ACID ETHYL-1 DIFLUORO-6,8 DIHYDRO-1,4 (METHYL-3 PIPERAZINYL-1) -7 OXO-4 QUINOLE CARBOXYL-3, OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THIS COMPOUND, AS AN ESSENTIAL ACTIVE MICROBICIDE INGREDIENT OF THIS COMPOSITION; AND - A QUANTITY CAPABLE OF RENDERING THE ISOTONIC SOLUTION OF A COMPOUND CHOSEN FROM POLYALCOOLS AND BORIC ACID, AS AN AGENT INTENDED TO MAKE THE SOLUTION ISOTONIC, THE PH OF THE SAID SOLUTION BEING ADJUSTED TO A VALUE OF APPROXIMATELY 3 At 6.5.

Description

AQUEOUS SOLUTION CONTAINING ORINOLONE CARBOXYLIC ACID

  The present invention relates to a stable isotonic aqueous solution of a biocidal substance which is a specific quinolone carboxylic acid, or a salt thereof. During these last years, a progress

  remarkable has been done in the field of anti-

  synthetic microbials, particularly those

  present in the form of quinolone carboxylic acids.

  The quinolone carboxylic acid derivatives according to the

  present invention are described in US Pat.

  United States of America No. 4,528,287, issued July 9, 1985, and in Japanese Kokai Patent Application No. 60-64979. In order to be used for injectable, ophthalmic or intranasal solutions, ear drops, or other aqueous pharmaceutical solutions, these compounds must be sufficiently soluble in water and their aqueous solutions must be isotonic and stable to light and light. heat. Microbicidal solutions containing the quinolone carboxylic acid derivatives according to the present invention are described in Japanese Patent Application Kokai 61-180771. According to this document, the solutions are adjusted to a basic pH, that is, to a pH of 8 to 11, in order to obtain stability. However, in general, it is preferred that the aqueous formulations are in conditions of neutral or weakly acidic pH. For the preparation of injectable, ophthalmic, or other pharmaceutical solutions, it is likewise preferred to employ neutral or slightly acidic conditions so as to render the osmotic pressure isotonic and thereby avoid irritation and tissue damage. However, when one attempts to render the compound according to the present invention isotonic with an isotonic agent selected from sodium chloride, potassium chloride, or other usual compounds and the like, the maximum concentration of this compound becomes

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  less than the concentration at which it exhibits pharmaceutical activity, and a desirable aqueous formulation can not be obtained. Now, according to the present invention, an aqueous, isotonic and stable solution is obtained in the following manner: To the compound which is 1-ethyl-6,6-difluoro-1,4-dihydro (3-methyl-1-piperazinyl) 4-oxo-4-quinoline-3-carboxylic acid, represented by the following formula, designated as the compound (I), F

F / COOH

HN \ N N (I)

HN F CH.

  Or a pharmaceutically acceptable salt thereof, (in any order> water and a polyhydric alcohol are added

  or boric acid, to make the solution isotonic

  and adjust the pH of the solution to a value

from 3 to 6.5.

  By research to provide isotonic, stable and non-irritating aqueous solutions containing the compound (I), or a salt thereof, it has been found that the desired aqueous isotonic solution can be successfully prepared by introducing a polyalcohol. or boric acid to make the solution isotonic, and then adjusting the pH to 3 to 6.5. Thus, under the conditions of the present invention, the compound <(I) immediately exhibits a solubility in water which is increased in the pH range below about 6.5 or

  pH values above about 3, for example, the solubility of

  above the required or appropriate concentration (approximately 0.3% w / v> for ophthalmic solutions and ear drops.) In contrast, the compound exhibits a solubility in water which is reduced to the desired pH ranging from from 3 to 6.5 when attempting to use sodium chloride, potassium chloride, or similar usual isotonic agents.However, as a result of further research, it has been discovered that use of a polyhydric alcohol or boric acid as isotonic agent leads to an isotonic aqueous solution,

  stable, with a suitable solubility of at least

  above the necessary and appropriate concentration and at

correct pH level.

  The aqueous solution according to the present invention

  It is useful as an injectable solution, for ear drops, as an intranasal or ophthalmic solution, or the like, containing in each case the compound I, or a salt thereof, having a broad antibacterial spectrum for microorganisms. gram-positive

and gram-negative.

  The compound <(I) can be used in the form of the free basic compound or in the form of a salt of this compound with a mineral base (eg, NaOH, KOH, etc.), with an organic base (e.g. , mono-, di-, trialkyl-amine, etc.), with a mineral acid (for example, HCl, HNO3, etc.), with an organic acid (for example, acetic acid, citric acid, etc. .). Glycerol, mannitol, glucose, xylitol, xylose, sorbitol and propylene glycol are exemplified as suitable polyalcohols. The concentration of the compound (I), or salt thereof, is from about 0.01% to about 10%, preferably from about 0.3% to about 5% w / v. There is enough polyalcohol or boric acid, or both, to make the solution isotonic; for example, boric acid is used in an amount of about 1.9%, glycerol in an amount of about 2.6%, mannitol in an amount of about 5.1%, and glucose. in an amount of about 1%. Boric acid is preferably used only

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  for topical preparations, because it has a higher toxicity than the optimal toxicity. The pH of the aqueous solution is between 3 and 6.5, with the range from 4 to 6.5 being preferred. The pH adjustment is carried out by any standard procedure, for example by the use of an organic or inorganic acid or a base

organic or mineral.

  Inasmuch as they are compatible with the objectives of the present invention, excipients employed for usual aqueous solutions, for example buffers for adjusting the pH <phosphate buffer, borate buffer,

  citrate buffer, acetate buffer, etc.), preservatives

  (benzalkonium chloride, p-hydroxybenzoate, benzyl alcohol, p-chloromethoxyphenols, chlorocresols, phenethyl alcohol, sorbic acid or its salts, methylosal, chlorobutanols, etc.), chelating agents <sodium edetate, sodium citrate, sodium phosphate condensed sodium,

  etc.) can be added to, and / or be present in

  commonly used in the aqueous solution of the present invention. These substances can be premixed in the aqueous solution, mixed with the polyalcohol or the acid

  boric, or added later.

  Depending on the case, one can first prepare an aqueous solution with polyalcohol or boric acid and

  excipients and then add the compound (I) or its salt.

  In each case, an appropriate procedure can be chosen.

  wherein at least one of the polyalcohol and boric acid is introduced into the acid solution of the compound (I)

  or a salt of this compound. Other medicinal ingredients

  apart from the compound (I) or a salt thereof,

  can also be added, if desired.

  The following examples illustrate the formulations according to the present invention, their preparation and their utility; however, they should not be considered

  as limiting of the present invention.

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Example A

  The effect of the isotonic agents on the solubility of the compound (I) * HCl To a mixture of water and isotonic agents, compound (1) * HCl was added to prepare a 2% w / v solution, and followed by pH adjustment to 5 with NaOH solution. The solution thus obtained was shaken in a thermostat for 24 hours. After filtration with a 0.45 μm filter, the content of the compound (I) * HCl in the solution was measured by the

  high performance liquid chromatography (HPLC) method.

  The pH value after filtration was 5. The results are shown in Table I.

Table I

  Isotonic agent Solubility of (concentration> compound <(I) * HC1 None 1, 3% NaCl (0.9%) 0.16% KCl (1.2%) 0.17% Boric acid (1.9%) 1 , 3% Glycerol (2.6%> 1.2% Xannitol (5.1%) 1.3% Glucose (5.1%) 1.3% The usual agents NaCl and KCl reduce the solubility, but glycerol, mannitol and glucose do not

do not reduce solubility.

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  Example B3 Stability Test The following formulations were encapsulated in a polypropylene container and stored under the conditions described, as shown in Table II. Samples were taken at the times indicated in Table II, and the appearance, pH, and percentage change in concentration of the <(I) * HCl compound were determined. The concentration of the compound (I) * HCl was

  measured by high speed liquid chromatography.

  Formulation Compound (I) * HCl ................... 0.3 g Glycerol concentrate.

  ............... 2.4 g EDTA * 2Na .......................... 0, 01 g Benzalkonium chloride ..... ....... 0.002 g NaOH ........................ sufficient quantity Purified water sterilized. ..... qs. per 100 ml pH 6..DTD: Table IL

  Proportion pH Appearance remaining (% I) Initially 100.0 6.0 colorless and transparent

Temperature 1 month 100.0 6.0 -

  ambient 2 months 100.0 6.0 3 me; 99.6 6.0 40.C 1 mej 100.0 6.0 2 me 100, 0 6.0 3 months 99.4 6.0 'C 1 month 99.9 6.0 Diffuse ambient light 1 month 98, 7 6.0

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  As shown in Table II, no significant change in color, precipitation, pH, or decrease in

active ingredient.

  The salts of the compound (I) with an organic or inorganic acid, other than the hydrochloride, presented the

  same effects as those shown in Tables I and II.

  Example 1. Ophthalmic Solution, Ear Drops and Intranasal Solution: Compound <I) * HCl ..................... 0.3 g Concentrated Glycerol ..... ................ 2.4 g EDTA * 2Na ...........................

  0.01 g Benzalkonium chloride ............... 0.002 g NaOH .............. DTD: ......... sufficient quantity Purified and sterilized water .... qs per 100 ml pH 6 xeple Ophthalmic solution: Compound <I)> * HCl .................. DTD: ... 0.3 g Boric acid ..... ..................... 1,8 g Sodium edetate ...................... 0.01 g Methyl parahydroxybenzoate ......... 0.02 g NaOH ........................ sufficient quantity Purified water sterilized ........ q.s. per 100 ml pH 6..DTD: 8 2609394

  Example 3. Solution for injection: Compound <I) ........................... 0.3 g Mannitol ....... ....................... 4.8 g NaOH .................

  ..... sufficient quantity Purified water sterilized ....... q.s. In conclusion, it is apparent from what has just been explained that the present invention proposes a solution .DTD: aqueous isotonic, new and useful, with micro-activity.

  bicide, 1-ethyl-6,6-difluoro-1,4-dihydro-4 (3-methyl-piperazinyl) -7-oxo-4-quinolinecarboxylic acid, or a salt thereof, having a broad sphere of utility, and having the features and benefits

previously listed.

  It is understood that the present invention should not be limited to the exact details of implementation, or the exact compounds, compositions, methods, procedures or embodiments that have been presented and described, and that any desirable modifications may be made without departing from the scope of the present invention.

Claims (4)

  1 - Stable isotonic aqueous solution   in that it essentially comprises: - an effective microbicidal amount of the compound which is 1-ethyl-6- (1,4-difluoro-1,4-dihydro-1-methyl-1-piperazinyl) -4-oxo-4-quinoline carboxylic acid; -3, or a pharmaceutically acceptable salt thereof, as the essential active microbiocidal ingredient of this composition, and; an amount capable of rendering the isotonic solution of a compound chosen from polyalcohols and boric acid, as an agent intended to render the solution isotonic, the pH of said solution being adjusted to a value of about 3 to 6.5.   2 - Solution according to claim 1, characterized   rised by the fact that the amount of the micro-ingredient   essential active bicide ranges from 0.01 to 10 percent by weight by volume.   3 - Solution according to claim 2, characterized   rised by the fact that the amount of the micro-ingredient   essential active bicide ranges from about 0.3 to about 5 for percent by weight by volume.   4 - Solution according to claim 3, characterized   rised by the fact that its pH is 4-6.5.   Solution according to Claim 4, characterized in that the essential active microbiocidal ingredient is 1-ethyl-6- (6-dihydro-1,4-dihydro-1-methyl-1-piperazinyl) -7-oxohydrochloride. -4 quinoline 3-carboxylic acid.